10-75399344-G-C

Variant names:

• chr10-75399344-G-C
• rs1043313899
• NM_032772.6:c.1346C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032772.6(ZNF503):​c.1346C>G​(p.Ala449Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A449V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF503 NM_032772.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.97
• Publications: 0 publications found

Genes affected

ZNF503 (HGNC:23589): (zinc finger protein 503) Predicted to enable metal ion binding activity. Involved in G1 to G0 transition involved in cell differentiation; negative regulation of cell population proliferation; and negative regulation of gene expression. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000270087 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28797042).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032772.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF503	NM_032772.6	MANE Select	c.1346C>G	p.Ala449Gly	missense	Exon 2 of 2	NP_116161.2
	ZNF503	NR_120651.2		n.812+1761C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF503	ENST00000372524.5	TSL:1 MANE Select	c.1346C>G	p.Ala449Gly	missense	Exon 2 of 2	ENSP00000361602.4	Q96F45-1
	ENSG00000270087	ENST00000418818.6	TSL:3	n.142+1761C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452542 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109752

Other (OTH) AF: 0.00 AC: 0 AN: 60000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.34	N
PhyloP100		9.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.21
Sift	Benign	0.091	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.20		Gain of loop (P = 0.0045)
MVP		0.068
MPC		0.58
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.34
gMVP		0.27
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1043313899; hg19: chr10-77159102;